Response to SMAC mimetics in patient-derived models of triple-negative breast cancer relies on RIPK1 activation
6 affiliations
- 1Department of Oncological Sciences, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT 84112
- 2Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT 84112
- 3Department of Biomedical Informatics, University of Utah, 421 S Wakara Way #140, Salt Lake City, UT 84108
- 4Department of Pharmacology and Toxicology, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112
- 5Applied and Developmental Research Directorate, Frederick National Laboratory, 1050 Boyles Street, Frederick, MD 21702
- 6Department of Surgery, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT 84112
Abstract
Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive breast cancer subtype with limited targeted treatment options. Second mitochondrial activator of caspases (SMAC) mimetics represent a promising therapeutic class for TNBC patients, although they have yet to be approved clinically. Screening a repository of 69 breast cancer patient-derived xenograft organoid (PDxO) lines revealed that approximately 39% were sensitive to the SMAC mimetic birinapant. To define the basis of resistance in lines that did not respond, we compared birinapant-sensitive (S-) and de novo resistant (R-) TNBC PDxOs. Birinapant caused degradation of inhibitor of apoptosis proteins (IAPs) in both groups but failed to induce cell death in R-PDxOs. We determined that R-PDxOs were susceptible to certain types of apoptosis but were specifically resistant to TNFR-mediated cell death, an integral pathway involved in SMAC mimetic response. Moreover, RIPK1 activation via autophosphorylation, a critical event in TNFR-mediated apoptosis, was absent in both R-PDxOs and PDxOs selected for acquired birinapant resistance. Pharmacologic inhibition or degradation of RIPK1 protected S-PDxOs from birinapant-induced cell death, demonstrating that RIPK1 activation is required for response in TNBC. To investigate how to restore RIPK1 activation in R-PDxOs, we discovered that HOIP, an E3 ubiquitin ligase that inhibits RIPK1 autophosphorylation, was more abundant in R-PDxOs compared to S-PDxOs. Inhibiting HOIP activity restored RIPK1 autophosphorylation and sensitized a subset of R-PDxOs to birinapant. Together, these findings identify impaired RIPK1 autophosphorylation as a mechanism of birinapant resistance in TNBC and suggest that RIPK1 activation state may distinguish SMAC mimetic-sensitive and -resistant tumors. Targeting HOIP may provide a strategy to overcome resistance in selected tumors.
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BibTeX
@misc{brown2026response,
title = {{Response to SMAC mimetics in patient-derived models of triple-negative breast cancer relies on RIPK1 activation}},
author = {Elisabeth Brown and Paige Jensen and Chieh-Hsiang Yang and Emilio Cortes Sanchez and Zhengtao Chu and Huiyi Yang and Yi Qiao and Martin Golkowski and Apurva Srivastava and Bryan E. Welm and Jaime Fornetti and Alana L. Welm},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761582},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761582v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Response to SMAC mimetics in patient-derived models of triple-negative breast cancer relies on RIPK1 activation
AU - Elisabeth Brown
AU - Paige Jensen
AU - Chieh-Hsiang Yang
AU - Emilio Cortes Sanchez
AU - Zhengtao Chu
AU - Huiyi Yang
AU - Yi Qiao
AU - Martin Golkowski
AU - Apurva Srivastava
AU - Bryan E. Welm
AU - Jaime Fornetti
AU - Alana L. Welm
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761582
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761582v1
AB - Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive breast cancer subtype with limited targeted treatment options. Second mitochondrial activator of caspases (SMAC) mimetics represent a promising therapeutic class for TNBC patients, although they have yet to be approved clinically. Screening a repository of 69 breast cancer patient-derived xenograft organoid (PDxO) lines revealed that approximately 39% were sensitive to the SMAC mimetic birinapant. To define the basis of resistance in lines that did not respond, we compared birinapant-sensitive (S-) and de novo resistant (R-) TNBC PDxOs. Birinapant caused degradation of inhibitor of apoptosis proteins (IAPs) in both groups but failed to induce cell death in R-PDxOs. We determined that R-PDxOs were susceptible to certain types of apoptosis but were specifically resistant to TNFR-mediated cell death, an integral pathway involved in SMAC mimetic response. Moreover, RIPK1 activation via autophosphorylation, a critical event in TNFR-mediated apoptosis, was absent in both R-PDxOs and PDxOs selected for acquired birinapant resistance. Pharmacologic inhibition or degradation of RIPK1 protected S-PDxOs from birinapant-induced cell death, demonstrating that RIPK1 activation is required for response in TNBC. To investigate how to restore RIPK1 activation in R-PDxOs, we discovered that HOIP, an E3 ubiquitin ligase that inhibits RIPK1 autophosphorylation, was more abundant in R-PDxOs compared to S-PDxOs. Inhibiting HOIP activity restored RIPK1 autophosphorylation and sensitized a subset of R-PDxOs to birinapant. Together, these findings identify impaired RIPK1 autophosphorylation as a mechanism of birinapant resistance in TNBC and suggest that RIPK1 activation state may distinguish SMAC mimetic-sensitive and -resistant tumors. Targeting HOIP may provide a strategy to overcome resistance in selected tumors.
SN - 2692-8205
ER -